1. Field of The Invention
The present invention relates to the use of selected chiral carbohydrates in cancer therapy and processes for their application. More particularly, the invention relates to the use of L-isomers of monosaccharides having cytotoxic and cytostatic properties. The selected compounds may be used alone or as an adjunct to other forms of cancer therapy. They are useful in conjunction with major forms of cancer therapy including surgery, biological and chemical therapies, radiation therapy, and hyperthermia. The administration of therapeutically effective amounts of L-monosaccharides increases the susceptibility of neoplastic cells to toxic elements. In addition to increasing mortality rate of neoplastic cells, these agents reduce the metastatic potential of the tumor, and slow the growth of the malignancy.
2. Description of Related Art
It has been estimated that well over one million new cases of cancer will be diagnosed in 1993 and over 5,000,000 people will succumb to the disease. The causes of cancer are complex and involve an elaborate interplay between environmental factors and the genetic material of the cell. Environmental factors involved in the development of cancers may be chemical, physical or biological in nature. Among the environmental factors are three major physical carcinogens, namely ionizing radiation, ultraviolet radiation and the presence of foreign bodies such as asbestos. Chemical carcinogens, both natural and man-made, tend to be compounds which complex directly with DNA and introduce errors in the DNA base sequence during replication. Biological factors include viruses, parasites, and hormones which have been implicated in mammalian carcinogenesis.
Cancer is a disease that develops when the orderly relationship between cell division and cell differentiation becomes disoriented. In normal mammalian systems the proliferation of cells is restricted to non-differentiated stem cells which ordinarily reproduce to replace mature, differentiated cells. As the proliferating stem cell differentiates, it loses the capacity to divide and reproduce. Conversely, in a cancerous system, dividing cells generally lose the capacity to differentiate and, with it, any natural constraints on their ability to reproduce.
Cancers arising in tissues having ectodermal or endodermal origins are generally called carcinomas while those derived from glands are called adenocarcinomas. Cancers arising in tissues derived from the mesoderm are called sarcomas while those of lymphhematopoietic origin are lymphomas and leukemia. Though they occur in many different types of tissue and exhibit different characteristics the primary features shared by most malignancies are anaplasia, invasion, and metastasis.
Initially cancer develops in a single cell which has been transformed through some external factor. In some cells, a single mutational event can lead to neoplastic transformation, but for most tumors it is evident that carcinogenesis is a multi-step process. The vast majority of human cancers appear to involve the accumulation of genetic damage and eventual transformation of the affected tissue. Following the transformation of the cell, tumor initiation begins with development of a clonal cluster of independently proliferating cells. In this phase no tissue destruction is evident, but cancer cells are present at their site of origin. Neoplastic cells may associate to form solid tumors or be widely disseminated in physiological systems such as bone marrow or lymphatic neoplasms. In the case of solid tumors the tissue can acquire the ability to metastasize and invade distal areas of the body through the bloodstream or lymphatic system.
The specific histology of the tumor and progression of the cancer often determine what form of treatment or combination of treatments will be used to treat the disease. Major approaches to the treatment of cancer involve surgery, radiation therapy, chemotherapy, hypothermia and immunotherapy using biological agents. These modalities often complement each other and are commonly used together, producing synergistic effects. Surgery, radiation and hyperthermia are the most effective in treating localized malignancies and together result in a cure in about 40% of all newly diagnosed cases. However non-localized neoplasms and metastatic tumors dictate the use of chemical or biological based therapies which operate throughout the body. Systemic administration of a combination of chemotherapeutic agents may cure another 10% to 15% of all patients. However, while advances in cancer treatment have been achieved using integrated therapeutic strategies, efficacious limitations still exist and patient results are often less than satisfactory.
Radiation therapy has proven effective in controlling a variety of tumors and is used in over half of all cancer cases. In addition to being used in conjunction with surgery, it often comprises the primary treatment for a number of tumor types including breast cancer, head and neck cancer, cervical cancer, brain tumors, lung cancers and certain stages of lymphoma. In general there are two major methods for delivery in radiation: teletherapy wherein external beam of radiation is aimed at the tumor site and brachytherapy, where the radiation sources are placed within or near the target. Different levels or particular forms of radiation, each of which has advantages for specific clinical situations, can be used to facilitate local control of tumor growth. As such, radiation therapy may be tailored to reflect the type of tumor or the individual needs of the patient.
Despite these advantages, the use of radiotherapy is still constrained by limitations inherent in the process. Normal tissues vary a great deal in the amount of radiation they can safely tolerate, and this tolerance limits the total acceptable dose of radiation. Moreover, radiation will kill only those cancer cells that receive sufficient linear energy transfer in the presence of molecular oxygen. The ionization of oxygen is believed to produce free radicals which are toxic to the neoplastic cells. Yet, many tumors occur in regions of tissue containing cells which are poorly oxygenated and prove to be relatively radiation resistant. It has been reported that these hypoxic cells may be less radiosensitive by a factor of up to three. As a result, hypoxic cell sensitizers are being tested in an effort to improve the therapeutic effects of tolerable doses of radiation. Nevertheless radioresistance still remains a primary impediment to effective preferential killing of cancer cells.
Like radiotherapy, chemotherapeutic agents are toxic compounds and exert their greatest anti-tumor effect when employed at the maximum tolerated dose. Different classes of drugs are used to kill tumor cells by different mechanisms and are commonly employed for the treatment of metastatic disease or non-localized tumors. With a chemotherapeutic agent, as with radiation therapy, toxicity to normal tissue limits the amount that can be safely administered. The main factors limiting the success of any chemotherapy are the inability to deliver the agents with adequate dose intensity and the development of drug resistance. Theoretically, small increases in the amount of drug delivered or increased sensitivity of the malignant cell could markedly improve the outcome. As such, a major focus in cancer research is the development of techniques to deliver chemotherapeutic agents with a higher dose intensity. Since the drug tolerance of healthy cells limits the absolute amount of chemotherapeutic agent which can be delivered, much of the effort has been directed towards making cancer cells more sensitive to the drugs.
The best chemotherapeutic agents discovered to date are only partially selective in their toxicity. The most efficacious agents interfere with important cellular systems such as DNA synthesis through the disruption of the action of critical enzymes or the availability of their substrates. However even the most effective agents are limited by natural resistance and non-specific effects on healthy cells. Drug resistant malignancies can result from poor transport to the cell, poor activation of the drug, inactivation of the drug, or altered pools of competing biochemical substrates. Further, since the differences between malignant and non-malignant cells are largely quantitative, some injury to normal tissue is inevitable during treatment. By selectively sensitizing the tumor cells both of these difficulties could be overcome and current chemotherapy rendered that much more effective with less patient discomfort.
As with both radiation and chemotherapy, hyperthermia has been shown to be tumoricidal in vitro and in vivo and has given encouraging results in clinical trials. Selective destruction of neoplastic cells appears to be a result of their sensitivity due to their active cellular metabolism. Among other effects, hyperthermia can cause irreversible damage to cancer cell respiration and interfere with synthesis of nucleic acids and proteins. In addition hyperthermia often disrupts the membrane of the malignant cells leading to their apparent autolytic destruction. It is thought that the subsequent modification of the tumor bed environment also contributes to the destruction of cancerous growths.
In addition to the direct cytotoxic effects of hyperthermia, heat is known to sensitize tissue to ionizing radiation. While hypoxic cells are as sensitive to hyperthermia as oxygenated cells, hyperthermia may inhibit the ability of hypoxic or partially hypoxic cells to recover from sublethal radiation injury. Many studies employing hyperthermia at 41.degree. C. to 43.degree. C. with low dose radiation have achieved remarkable regressions when compared with hyperthermia alone. Further, hyperthermia has often been found to increase the efficacy of anti-cancer drugs by altering the cellular environment and resulting metabolism. In addition it has been reported that hyperthermia may stimulate an immunological response by increasing the exposure of tumor antigens.
Selective stimulation of a patient's immune system to combat neoplasms has become an increasingly potent weapon as the discovery of tumor specific antigens has increased in recent years. Immunotherapy, consisting of both humoral and cell-mediated responses may be stimulated generally or directed at select antigens unique to cancer cells. Once a tumor cell expresses a recognizable antigen, antibodies, phagocytes, natural killer cells, cytotoxic T lymphocytes and lymphokine-activated killer cells may all be employed to eliminate the exposed malignancy. While immunotherapy has been very successful in treating non-localized neoplasms such as leukemia, it has not proved as efficacious against solid tumors. Therefore immunotherapy is often used in combination with other treatments or for suppression of metastasis following the elimination of a localized tumor.
Whichever form of treatment or combination thereof is selected, it is predicated on exploiting the differences between healthy cells and neoplastic cells. Transformed cells exhibit a number of biochemical and regulatory anomalies in comparison with healthy cells, providing an approach for non-surgical cancer treatments. For instance transformed cells often express anomalous glycoproteins on the cell surface, leading to insufficient environmental modulation of their activities. These modified proteins may preclude normal contact inhibition and tissue recognition thus allowing the cancer to spread. Yet at the same time they may also constitute a unique surface antigen. Such antigens serve as a marker and greatly facilitate the detection and eradication of a malignancy. Another important therapeutic distinction is the relatively rapid division of cancerous cells and corresponding increase in the rate of cellular metabolism. With the exception of immunotherapy, most cancer treatments tend to exploit some aspect of this accelerated reproduction to selectively terminate neoplastic cells.
To support this elevated reproductive rate cellular metabolic processes undergo a corresponding increase in tempo. It is well documented that transport systems used in the uptake of such needed nutrients as sugars, amino acids and nucleosides frequently function at higher capacity in transformed cells. Transport of glucose, its non metabolizable analogues dioxyglucose and 3-0-methyl glucose, mannose, galactose, and glycocyamine all increase with transformation. In addition, transport of certain amino acids, such as glutamine, arginine and glutamic acid are escalated. Even analogues that are not incorporated into proteins such as cycloleucine and alpha-amino isobutyric acid also experienced increased uptake after transformation of cultured cells. This massive influx of nutrients appears to continue regardless of the efficiency of cellular reactions or the actual rate of production of essential cellular components.
For instance, cancer cells are known to consume large amounts of glucose as a source of energy permitting the exaggerated use of amino acids and nucleosides in the synthesis of DNA. Further, it has been shown that many cancers are almost entirely dependant on glucose for their energy requirements. Exploiting this trait by supplying excess glucose, the aerobic glycolysis of tumor cells can be stimulated in vivo to a very high extent. However, due to substrate deficiencies, it appears that many cancer cells take in much more glucose than they can metabolize efficiently and, as a consequence, excrete large amounts of lactic acid. This leads to a lower pH value in the malignant cells which can increase the susceptibility of the tumor to various therapies.
Accordingly, it is an object of the invention to provide a means for producing cytotoxic and cytostatic effects in neoplastic tissue without injuring healthy cells.
It is a further object of the present invention to enhance the cytotoxic and cytostatic effects of cancer therapies.
It is another object of the present inventions to provide compositions useful for the reduction or elimination of malignant tissue in a mammalian system.